Nonsteroidal anti-inflammatory drugs (NSAIDS) have marked colon cancer (CRC) chemopreventive benefits as shown in epidemiological, experimental and clinical trials. However, to achieve a modest 30-50% risk reduction, the therapy needs to be extensive and spread over a long period. This exposes subjects to unintended consequences of NSAIDS-related toxicity such as ulcers, GI bleeding, hemorrhagic strokes etc. This may be particularly problematic in subjects displaying no significant chemopreventive response. How and why individuals respond to chemoprevention differently is unclear. It is conceivable that these differences may arise from innate gene-environment interactions (G X E; reflecting genetics and lifestyle factors of an individual) that may present unique biological milieu to affect NSAIDS sensitivity. These differences may be more noticeable in gender specific CRC (with women having higher prevalence of proximal lesions, DNA mismatch repair deficient tumors etc.) that are influenced by both genetic and environmental factors (diet, obesity, exercise, alcohol and tobacco use etc.). Indeed, our group has reported that women have altered susceptibility to both genetic and environmental CRC risk factors [3] which may possibly translate into altered responsiveness to chemoprevention. Some epidemiological studies do suggest that women have a stronger anti-cancer response to NSAIDS then men, although there may be confounding from gender specific lifestyle factors. To enhance population-wide risk-benefit of NSAIDS related chemoprevention, it is therefore essential to improve the population selection process based on markers that reflect influence of gene-environment interactions especially with respect to gender. Opportunely uninvolved normal appearing colonic mucosa represents a powerful resource for the gene-environment interface markers that can act as biological sensors for cancer risk. Therefore, for personalized NSAIDS chemopreventive risk-benefit analysis, in vitro model of colonic mucosal cell cultures developed from colonic tissue (that take into consideration influences of the individual's G X E interactions) have a great potential for gaging individual's NSAIDS responsiveness. These studies can provide some insights into the biological modifiers of early CRC development and chemoprevention especially in relation to gender. Clinically, by understanding the intricate mechanisms of these differential responses to chemoprevention, we would potentially develop individualized screening decisions through a minimally intrusive assay (i.e. rectal swab). This is critical given that even if we may double CRC risk, the vast majority (~90%) will never develop CRC yet are subjected to potentially unnecessary procedure associated costs, pain and potential complications of colonoscopy or the toxicity of NSAIDS. Thus, this proposal could potentially be highly significant from both a biological and public health perspective.